Previously, it has been known to prepare certain bulk sol-gel materials for use in orthopedics and in certain other therapeutic regimes. In some cases, pharmaceutically active moieties, such as bone morphogenic protein, antibiotics and other species have been included in such bulk sol-gels. These materials have been proposed for use in the body of patients, e.g. for use in surgery such as spine and other orthopedic surgery as well as for use in drug delivery intracorporeally. The preparation of sol-gels generally as well as sol-gels having pharmaceutically active species in them has been disclosed in a number of U.S. patents, including several assigned to the assignee of this invention. These include U.S. Pat. Nos. 5,874,109; 5,849,331; 5,817,327; 5,861,176; 5,871,777; 5,591,453; 5,830,480; 5,964,807; and 6,569,442. Each of these is incorporated herein by reference in order to set forth a number of ways of preparing sol-gels generally useful to the present invention, especially certain sol-gels having pharmaceuticals included within them.
The foregoing sol-gel bulk materials have been included in tissue engineering devices for spine surgical use and in other products proposed for surgical use. These bulk sol-gel derived materials were produced by a room temperature process that included the formation of acid-catalyzed liquid sols, followed by casting, gelation, ageing and drying. Biomolecules could be mixed into the liquid sols to become encapsulated in the resulting solids, which could be formed into discs or granules. The molecules which were incorporated this way were released in a controlled manner and maintained their biological activity. The sol-gels are acceptably stable for such uses and are known to leach out medicaments from their porous structure over periods of time. They are not physically robust and, overall, cannot be used in relatively thin coatings, however.
One of the foregoing patents, U.S. Pat. No. 5,817,327, describes an surgical implant with a sol-gel derived coating. This coating was made of porous silica glass; biologically active molecules, such as antibiotic, were included. However, the disclosed sol-gel process includes the formation of a liquid sol followed by casting, gelation, aging, and drying—all steps which, while suitable for the manufacture of bulk materials, were not satisfactory for the elaboration of practical medical device coatings or useful films for composites. Moreover, the properties, such as the porosity, displayed by sol-gel derived structures made in this way are not appropriate for use in thin films as part of composite implants and the like. A much lower porosity is needed.
Sol-gels are known per se as are many of the overall chemistries which can be used to prepare them. A convenient work summarizing sol-gel technology is Brinker, et al., Sol-Gel Science—The Physics and Chemistry of Sol-Gel Processing, Academic Press, 1990. Chapter 13 of this work, which chapter is specifically incorporated herein by reference, discusses the formation of certain kinds of films from sol-gels, typically, silica based films. The general teachings of Brinker does not provide a practical methodology for preparing the kinds of pharmaceutical delivering and other xerogel films as is desired. In particular, Brinker usually calls for a sintering step, which step is not desirable for use in the preparation of the composites of the present invention. Indeed, Brinker et al. focused on the effects of various processing parameters such as the sol composition (water concentration, alcohol concentration and pH of the sols); the incorporation of biomolecules was never considered. Thus, those authors never appreciated the need to alter processing properties to incorporate desirable quantities of medicaments, factors and other desirable therapeutic molecules in films for subsequent, controlled release—all while maintaining stability and mechanical adhesion to a substrate.
Böttcher et al, Sol gel composite films with controlled release of biocides, J. Controlled Release, vol. 60, page 57-65 (1999) used a sol-gel process for depositing thin films incorporated biocides. These include antimicrobial acids, such as benzoic, ascorbic and boric acids which are used for food and wood preservation. Alcohol solutions of biocides were added to water-free sols which by themselves had a high acid and alcohol content (alcohol/TEOS ratio>4). In a single-step process, the sols were applied to a polymeric foil to form a single-layer film. These one-layer films showed a short-term release: about 90% of the incorporated biocides were released within 10 hours.
The process described by Böttcher suffers from major limitations, and is not acceptable for preparing thin silica sol-gel films for the controlled release of therapeutic biomolecules. Among other things, the processes taught by Böttcher do not allow for using water, as is strongly desired for medicaments. Moreover, the amount of release of molecules is too small for practical use in pharmaceutics. Additionally, the release duration is too short and the adhesion of the films to metallic substrates is unsatisfactory for these purposes.
Risk of infection is considerable in open fractures and its prevention is challenging, especially when fracture fixation material is used. Bacteria can adhere to internal fixation nails that are used to stabilize the fractured bone and form a biofilm. The high resistance of the biofilm to systemic antibiotic treatment can necessitate further surgical procedures. One way to avoid this problem is to use a device that provides a controlled release of antibiotics. Sol-gel derived silica bulk xerogels have been disclosed as materials for the controlled release of antibiotics such as vancomycin. Radin S, Ducheyne P, Kamplain T, Tan B H. Silica sol-gel for the controlled release of antibiotics. I. Synthesis, characterization, and in in vitro release. J Biomed Mater Res 2001; 57:313-20; Aughenbaugh W, Radin S, Ducheyne P. Silica sol-gel for the controlled release of antibiotics. II. The effect of synthesis parameters on the in vitro release kinetics of vancomycin. J Biomed Mater Res 2001; 57:321-26.
These bulk xerogel materials were produced by a room temperature process, which included the formation of acid-catalyzed liquid sols followed by casting, gelation, aging, and drying. The antibiotic incorporated into liquid sols becomes encapsulated into resulting bulk xerogels shaped either as discs or granules. The antibiotic is released from these xerogels in a controlled manner and maintains its bactericidal activity in this bulk form.
There remains a great need for materials useful in surgery, in therapeutics, for the treatment of wounds and otherwise which effect the controlled release of pharmaceutically active molecules. It has long been desired to provide materials, e.g. which are bacteriostatic and can be used in emergent therapy for wounds. Other materials are desired for use in surgery, especially orthopedic surgery while still other uses involving such controlled release of medicaments will find immediate application in diverse therapeutic regimes.